Simultaneous Quantitation of S(+)- and R(−)-Baclofen and Its Metabolite in Human Plasma and Cerebrospinal Fluid using LC–APCI–MS/MS: An Application for Clinical Studies

Molecules

YashpalS. Chhonker¹  DarylJ. Murry¹  Qingfeng He¹  MatthewJ. McLaughlin² 

[1] Clinical Pharmacology Laboratory, Department of Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, NE 68198, USA;Division of Rehabilitation Medicine, Children’s Mercy Kansas City, UMKC School of Medicine, Kansas City, MO 64108, USA;

关键词: lc-ms/ms;    baclofen;    3-(4-chlorophenyl)-4 hydroxybutyric acid (chba);    chiral separation;    csf;    spasticity;    pharmacokinetics;   

DOI  :  10.3390/molecules25020250

来源: DOAJ

【 摘 要 】

Baclofen is a racemic mixture that is commonly used for the treatment for spasticity. However, the optimal dose and dosing interval to achieve effective cerebral spinal fluid (CSF) concentrations of baclofen are not known. Moreover, it is unclear if there are differences in the ability of R- or S-baclofen to cross the blood−brain barrier and achieve effective CSF concentrations. We have validated a liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method with improved selectivity and sensitivity for the simultaneous quantitation of R- and S-baclofen and metabolites in plasma and CSF. Protein precipitation by acetonitrile was utilized to obtain an acceptable recovery of the analytes. The detection and separation of analytes was achieved on a 48 °C-heated Crownpak CR(+) column (150 mm × 4.0 mm, 5μ) with elution using 0.4% formic acid (FA) in water and 0.4% FA in acetonitrile as the mobile phase running at a flow rate of 1.0 mL/min. Accurate quantitation was assured by using this MS/MS method with atmospheric pressure chemical ionization in multiple reaction monitoring (MRM) mode. Therefore, this method is enantioselective, accurate, precise, sensitive, reliable, and linear from 1 to 1500 ng/mL for baclofen and 2 to 4000 ng/mL for the metabolites. An additional method was developed to separate racemic baclofen 3-(4-chlorophenyl)-4 hydroxybutyric acid metabolites for individual concentration determination. Both validated methods were successfully applied to a clinical pharmacokinetic human plasma and CSF study evaluating the disposition of baclofen and metabolites.

【 授权许可】

Unknown